APVO436 Treatment Does Not Appear to Be Adversely Impacted by CRS or Interventional Steroids in AML/MDS

A phase 1b dose-finding study (NCT0364780) has demonstrated that cytokine release syndrome (CRS) developed in approximately 1 of 5 patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) treated with the CD123- and CD3-engaging bispecific antibody APVO436, but the events were well-managed with steroids.¹

According to findings that were presented in a poster at the ASH Annual Meeting and Exposition 2021, neither CRS nor interventional steroids had an adverse effect on outcomes.

“Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response is IL-6. In most cases, CRS events were transient and medically manageable with standard of care including the use of dexamethasone and tocilizumab [Actemra] or siltuximab [Sylvant],” lead study author Tara Lin, MD, a professor in the Department of Hematologic Malignancies and Cellular Therapeutics, director of the Acute Leukemia Program, and medical director of the KU Cancer Center Clinical Trials Office at the University of Kansas Medical Center, and coauthors wrote in the poster.

Prior findings from the phase 1b trial showed that APVO436 demonstrated encouraging activity and was generally tolerable in patients with relapsed/refractory AML and MDS although treatment-emergent CRS was reported in a proportion of patients.

To better understand the risk, severity, and biomarkers of treatment-emergent CRS in this population, investigators measured serum levels of proinflammatory cytokines and the longitudinal changes in serum cytokine levels and performed immunophenotyping on cryopreserved peripheral blood mononuclear cells.

The results showed that grade 3/4 CRS was the 6th most common grade 3 or greater adverse effect (AE), occurring in 4 patients (8.7%). CRS was reported as a serious AE in 7 (70%) of the 10 patients who developed CRS. Moreover, CRS led to dose interruptions in 4 patients, dose reduction in 1 patient, and permanent drug discontinuation in 1 patient.

Only 2 of the 46 patients experienced CRS-related dose-limiting toxicity.

Notably, 7 of the 10 patients with CRS did not develop neurotoxicity; only 3 patients developed CRS and neurotoxicity.

One patient with grade 2 CRS and neurotoxicity developed fatal acute kidney failure despite the use of tocilizumab that was likely caused by APVO436-related CRS.

Additional findings showed that overall survival was not significantly affected by CRS in the safety population. The average survival times were 169.1 ± 42.1 days in patients who developed CRS vs 173.9 ± 27.2 days in all other patients (P = .9).

Prophylaxis with steroids did not eradicate the risk of CRS. Of 4 patients who developed grade 3 or greater CRS, 2 received preemptive steroids. Notably, CRS did not show a clear dose-dependent relationship.

Further results showed a trend between older age and development of CRS (72.9 ± 1.6 years; [median, 73.5 years] vs 63.5 ± 2.3 years; [median, 65.0 years]; P = .04).

Notably, the percentage of T cells in the peripheral blood was not predictive of CRS although a statistically insignificant (P = .1) trend toward higher absolute lymphocyte count was observed in patients who experienced CRS.

Patients with a higher leukemia burden, defined by a higher white blood cell count, a higher percentage of blasts in the bone marrow, or a higher percentage of blasts in the peripheral blood did not have a higher rate of CRS.

Additional findings showed that 9 of 32 non-obese patients (28.1%) developed CRS, whereas only 1 of 13 obese patients (7.7%) developed CRS, reflecting a trend toward a lower risk of CRS in obese patients (P = .14). Only 1 of the 10 patients who developed CRS was obese, and the patient had grade 1 CRS for a total duration of 2 days without any tocilizumab use.

Moreover, the body mass index (BMI) of the 10 patients who developed CRS was not higher than the average BMI of patients who did not experience CRS.

“Our results do not indicate that obesity is a significant contributing factor to treatment-emergent CRS in APVO436-receiving patients,” wrote the coauthors.

Regarding the serum cytokine profiles of patients who developed CRS, there was a substantial and prolonged increase in serum IL-6 levels between days 1 and 6 following APVO436 administration.

Within 1 to 2 days following the first dose of APVO436, the mean serum IL-6 concentration was increased 145-fold over baseline (755 vs 5.2); at the end of 1 week, the serum IL-6 concentration was still increased 83-fold over baseline.

Comparatively, the increase in serum levels of IL-5, IL-10, MCP-1, and TNF-α were short-lived with a mild to moderate increase over baseline levels. Levels of IL-17A and IFN-γ did not show

substantial or prolonged increases.

In terms of CRS management, 6 patients received tocilizumab, 3 patients had dose reductions and/or dose delays, 2 patients had temporary interruption of APVO436, and 3 patients with grade 2 to 4 CRS discontinued APVO436.

No changes to dose or schedule were made in 1 patient who developed grade 1 CRS that resolved within a day.

In terms of clinical responses to APVO436 in patients who developed CRS, of the 39 patients with relapsed/refractory AML, 34 were evaluable for response.

Twelve patients (35.3%) had progressive disease (PD) and died of leukemia between 29 and 70 days (median, 43 days). Twenty-two of these 34 patients (64.7%) had stable disease (SD) as their best overall response. In 8 of these 22 patients, SD was achieved between 31 and 75 days following study entry and lasted approximately 3 months or longer.

Among the patients with favorable responses, 4 experienced CRS and 4 did not, and patients who did and did not experience CRS experienced prolonged stabilization of disease, partial remissions, and complete remissions following APVO436 infusions, indicating that APVO436-related CRS had no effect on clinical responses in patients with relapsed/refractory AML.

Moreover, the median survival was 188 days in patients with CRS and 151 days in those without CRS (Log-rang Χ2 = 0.042, P = .7), similarly indicating no effect on survival outcomes.

“Notably patients who developed CRS after APVO436 therapy were not more or less likely to have a favorable response. As patients received dexamethasone as a premedication and for treatment of CRS, these results suggest that dexamethasone does not prevent favorable responses to APVO436 at the applied dose level and schedule,” concluded the authors.

_Reference

_{Lin T, Watts JM, Mims AS, et al. Risk and severity of cytokine release syndrome in patients with relapsed/refractory (R/R) AML or MDS treated with CD3xCD123 bispecific antibody APVO436. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract 3416.}